Dissolution and Uniformity Properties of Ordered Mixes of Micronized Griseofulvin and A Directly Compressible Excipient

Ordered mixes of micronized griseofulvin were prepared with a commercially available directly compressible excipient. The excipient consisted of a combination of maltose and dextrose and a particle size fraction of approximately 250-850µ was employed in the mixing studies. Ordered mixes containing 0.25%, 0.5%, and 1% active ingredient were prepared and after thirty minutes of mixing, excellent content uniformity of the mixes was seen. Rapid dissolution of drug from the sugar granules was observed when the drug coated granules were tested using the U.S.P. Paddle Method. The ordered mixing process provided an even coat of the micronized drug onto the granules. As the granules dissolved, particle-particle interactions and aggregation problems with the hydrophobic drug were eliminated. The properties of griseofulvin tablets prepared from these ordered mixes were evaluated and the tablets showed excellent content uniformity and rapid dissolution of griseofulvin from the dosage form.     

Dissolution and Uniformity Properties of Ordered Mixes of Micronized Griseofulvin and A Directly Compressible Excipient

Abstract

Ordered mixes of micronized griseofulvin were prepared with a commercially available directly compressible excipient. The excipient consisted of a combination of maltose and dextrose and a particle size fraction of approximately 250-850µ was employed in the mixing studies. Ordered mixes containing 0.25%, 0.5%, and 1% active ingredient were prepared and after thirty minutes of mixing, excellent content uniformity of the mixes was seen. Rapid dissolution of drug from the sugar granules was observed when the drug coated granules were tested using the U.S.P. Paddle Method. The ordered mixing process provided an even coat of the micronized drug onto the granules. As the granules dissolved, particle-particle interactions and aggregation problems with the hydrophobic drug were eliminated. The properties of griseofulvin tablets prepared from these ordered mixes were evaluated and the tablets showed excellent content uniformity and rapid dissolution of griseofulvin from the dosage form.     

Tablet-to-Tablet Dissolution Variability and its Relationship to the Homogeneity of a Water Soluble Drug

The homogeneity of a water soluble drug in a tablet granulation was studied by mixing the granulated drug with excipients in a V-shaped tumbling mixer. Samples were withdrawn from five different locations of the mixer for homogeneity and dissolution studies at different mixing times. For dissolution studies, tablets were compressed at a constant compression load. Qualitatively, the coefficient of variation of mixing and dissolution looked similar, suggesting that the mixing homogeneity may have some relationship to the tablet-to-tablet dissolution variability. The addition of magnesium stearate resulted in an increase in the coefficient of variation of mixing and a decrease in the dissolution rate. A large decrease in the dissolution rate occured during the first minute of mixing with the magnesium stearate. The tablet crushing strength continuously decreased during the first 10 minutes of mixing with the magnesium stearate. The results suggested that the formulation in which a major portion of the excipients was not wet granulated with the drug resulted in higher tablet-to-tablet dissolution variability. The addition of sodium starch glycolate or sodium carboxymethyl cellulose to starch for enhancing disintegration neither improved the tablet-to-tablet dissolution variability nor increased the rate of drug dissolution.     

Effects of Lubricant Level, Method of Mixing, and Duration of Mixing on a Controlled-Release Matrix Tablet Containing Hydroxypropyl Methylcellulose

The effects of the lubricant magnesium stearate at different concentrations, mixing shear rates, and mixing times on the tablet properties and drug dissolution from controlled-release matrix tablets containing hydroxypropyl methylcellulose 2208, USP (METHOCEL® K4M Premium) have been studied. Diphenhydramine HCl and hydrochlorothiazide were chosen as the model drugs. Spray-dried hydrous lactose (Fast Flo Lactose-316®) and anhydrous dibasic calcium phosphate (A-TAB®) were chosen as the model excipient/fillers. The impact of magnesium stearate on the mechanical strength of tablets appeared to be dependent on the bonding mechanism of the components of the powder mix. Tablets containing A-TAB, which compacts via a brittle fracture mechanism, were harder and had significantly better friability patterns than those prepared using Fast Flo Lactose-316. The compaction of Fast Flo Lactose-316 appears to be a combination of brittle fracture and plastic deformation. Mixes containing lower levels of lubricant (0.2%) generated tablets that had higher crushing strengths than those with higher lubricant levels (2.0%). Drug release was impacted to the greatest extent by the solubility of the drug and excipient/filler but was only slightly affected by the level of magnesium stearate and duration of mixing.     

Effect of Flowing Adjuvants on the Homogeneity and the Kinetics of Mixing of Low Dosage Cohesive Powder Mixtures

One of the major problems encountered in powder mixing, depending on the properties of the constituents of the mix is the inability of low-power mixers to break down powder agglomerates

The effects of the addition of two flowing ad juvants (colloidal Aluminium oxide and Aerosil-200^R) on the homogeneity of cohesive powder mixtures and on the kinetics of mixing, were investigated

It was demonstrated that colloidal Aluminium oxide increases the degree of homogeneity of a 1 % Triamteren-200 mesh lactose mixture blended in a Turbula T2 C mixer, when an appropriate concentration of the adjuvant, corresponding to that which produces the best flowing properties of the excipient was used. Aerosil-200^R did not enhance the homogeneity of the mix     

Effects of Lubricant Level,Method of Mixing,and Duration of Mixing on a Controlled-Release Matrix Tablet Containing Hydroxypropyl Methylcellulose

Abstract

The effects of the lubricant magnesium stearate at different concentrations, mixing shear rates, and mixing times on the tablet properties and drug dissolution from controlled-release matrix tablets containing hydroxypropyl methylcellulose 2208, USP (METHOCEL® K4M Premium) have been studied. Diphenhydramine HCl and hydrochlorothiazide were chosen as the model drugs. Spray-dried hydrous lactose (Fast Flo Lactose-316®) and anhydrous dibasic calcium phosphate (A-TAB®) were chosen as the model excipient/fillers. The impact of magnesium stearate on the mechanical strength of tablets appeared to be dependent on the bonding mechanism of the components of the powder mix. Tablets containing A-TAB, which compacts via a brittle fracture mechanism, were harder and had significantly better friability patterns than those prepared using Fast Flo Lactose-316. The compaction of Fast Flo Lactose-316 appears to be a combination of brittle fracture and plastic deformation. Mixes containing lower levels of lubricant (0.2%) generated tablets that had higher crushing strengths than those with higher lubricant levels (2.0%). Drug release was impacted to the greatest extent by the solubility of the drug and excipient/filler but was only slightly affected by the level of magnesium stearate and duration of mixing.     

High Energy Ordered Mixture for Improving the Dissolution Rate of Sparingly Soluble Compounds

Bioavailability of a sparingly soluble drug is often limited by the rate of dissolution of the drug substance. The drug in a micronized form is generally employed to maximize the bioavailability. However, the micronized drugs tend to agglomerates and do not always exhibit an improved dissolution rate. In this study, a simple processing using a high energy mill was demonstrated as an effective means to utilize the entire surface area available for drug release of the micronized drug. An experimental hydrophobic drug in a micronized form was milled with a carrier, hydrous lactose using Micropulverizer to achieve a uniform mixture so-called “high energy ordered mixture”. The high energy ordered mixture provided a contact surface area taking part in dissolution 4-fold greater than the micronized drug agglomerates. Therefore, the dissolution was significantly improved, irrespective of test parameters such as agitation and the presence of surfactant. This high energy ordered mixture provided the advantages over a simple ordered mixture for: (i) complete deaggregation of the micronized drug to fine primary particles, (ii) improving the efficiency of the carrier by increasing contact surface area, and (iii) enhancing the bonding effect between the drug and lactose particles due to free water molecules released from the crystal lattices of hydrous lactose during milling. This procedure could be applied to overcome dissolution problems of sparingly soluble drugs with cohesive nature.     

Effects of Mixer and Mixing Time on the Pharmaceutical Properties of Theophylline Tablets Containing Various Kinds of Lactose as Diluents

Effect of mixing time on the flowability, compressibility, tablet hardness and dissolution of theophylline tablets was investigated using two types of mixers, i.e., twin-shell and high-speed mixers. Theophylline, three kinds of lactose ($aL-monohydrate, β-anhydrate and spray-dried product), disintegrator and magnesium stearate were mixed, and tablets were compressed. While the particles mixed with magnesium stearate by the high speed mixer were coated with magnesium stearate, those mixed by the twin-shell mixer formed an ordered mixture. The dissolution differed depending on the mixing time and method.     

Content Uniformity of Ethinyldestradiol Tablets 10 μG: Effect of Variations in Processing on the Homogeneity After Dry Mixing and After Tableting

Abstract

The effect of numerous processing factors such as mixer geometry and design, power input, time of dry and wet mixing on the content uniformity of tablets containing potent drugs have been studied. Cohesive drug powders and excipients have been used.

Results show that pharmaceutically acceptable hamageneity is achieved after dry mixing far 7 hours in the Lödige-Marton mixer. It is shown that there is no significant improvement of homogeneity on increasing the time of wet mixing in excess of 5 minutes, and the rate of breakdown of the drug agglomerates and dispersion of individual particles, under the experimental conditions, is very slow. The high energy input exerted by ball milling markedly improves the homogeneity of the powder mixes and the content uniformity of tablets. After 15 minutes of dry mixing, the state of homogeneity of the powder mix containing cohesive drug powder in minute amounts in cohesive excipient is not influenced by the type of mixer.     

Effects of Interparticulate Interactions on Mixing Homogeneity

Abstract

By theoretical approach, the highest degree of mixing of cohesive, interactive powders was derived to conform to the homogeneity of the random mixture of free-flowing, non-interactive constituents. Particulate interactions like adherence of a cohesive drug ingredient to the diluent component, cannot yield ordered mixtures of higher degree of homogeneity under real mixing conditions.

These conclusions were confirmed by mixing experiments, using minor proportions of free-flowing and of cohesive drug constituents, and diluents in excess. With both types of drug powders, the quality of the random mixture was attained. Ordered mixtures of higher degree of homogeneity could not be produced.     

Dissolution Characteristics of Interactive Powder Mixtures. Part One: Effect of Solubility and Particle Size of Excipients

Abstract

Interactive mixtures of fine cohesive drug powders and coarse free flowing excipients are reported to increase dissolution rates of poorly soluble drugs. However, dissolution rates are known to be affected by the solubility characteristics of the excipients as well as excipients surface characteristics after mixing with lubricant.

In this study the effects of solubility and particle size of excipients on dissolution of micronized griseofulvin from interactive powder mixtures were investigated. Quantitative assessment of dissolution from such mixtures showed that systems containing soluble excipients increased dissolution of the drug more efficiently than mixtures prepared using insoluble excipients. The role of the soluble excipient was more significant after mixing with magnesium stearate. Excipients of smaller particle sizes increased dissolution more efficiently than their large size counterparts. Effects of particle size were particularly significant in case of water insoluble excipients.     

Evaluation of Ludipress as a “Multipurpose Excipient” for Direct Compression: Part II: Interactive Blending and Tableting with Micronized Glibenclamide

In the second part of this publication the differing interactions of micronized glibenclamide during mixing with four filler/binders for direct compression were studied. The excipients used were: Ludipress, Cellactose, Avicel PH 200 and Karion Instant. In order to prepare interactive mixtures, increasing amounts of micronized glibenclamide were blended with filler/binder fractions of 125 to 500 μm. The degree of interactivity was determined by air jet sifting of the mixes, comparing drug content in the mixes before and after sieving. Cellactose showed the highest adhesion tendency for glibenclamide due to the large cavities in the particles, leading to a reagglomeration within these cavities. Tablets containing 1.75, 3.50, 5.00 and 10.00 mg of glibenclamide per tablet were compressed with Cellactose and Ludipress. As previously reported (1) for Cellactose based placebo tablets, Cellactose also showed a tremendous increase in disintegration time and a prolonged dissolution rate at compaction pressures above 100 MPa. The corresponding values of Ludipress were not influenced. Therefore in terms of a multipurpose-excipient, Ludipress should be given preference in the formulation of low dosed drugs.     

Predictive Stress Tests in the Scale-Up of Capsule Formulations

In early development, supplies of bulk active are limited and capsule formulations are developed on a small scale. However they should be suitable for scale-up. In this report, the Turbula T2C is shown to mimic the prolonged stirring and stressing of powder blends in the large hopper of a dosator type machine, e.g. Zanasi LZ64. The degree of mixing affects the lubricity and wettability of capsule blends containing magnesium stearate and stressing powder blends in a Turbula T2C highlights changes in blend properties which occur on scale-up. Measuring tapped bulk density, wettability and disintegration of stressed blends identifies robust formulations which are unaffected by long “lubrication” times and scale. Changes in blend properties are influenced more by shearing energy than the extent of mixing     

Mixing of cohesive pharmaceutical formulations in tote (bin) blenders

Experiments were conducted to determine the influence of process parameters such as fill level, mixing time, shear, and baffle presence along with material attributes such as initial active aggregate size and concentration on the homogeneity of a cohesive placebo formulation in a pilot plant scale tote blender. The formulation was a ternary system made up of microcrystalline cellulose, NaCl or KCl salt, and magnesium stearate. Blend homogeneity was evaluated by sampling the blend using core samplers. Salt concentration was quantified using a conductivity technique. After a brief transient mixture, homogeneity became insensitive to mixing time and initial active concentration, however, it was a strong function of fill capacity and initial active aggregate size. Sixty percent fill was found to be optimum. Active aggregate size had an adverse effect on mixture homogeneity. The best results were obtained when the salt aggregates were initially comparable in size to that of the excipient and a high shear pre-blending step was implemented prior to dilution in the tote blender. For the strongly agglomerating material examined here, pre-blending was only beneficial if the initial aggregate size was relatively small. For cohesive systems that form large and rigid aggregates, it is recommended to mill or screen the potentially agglomerating component and then mix the system in a blender equipped with an intensifier bar.     

A new experimental design method to optimize formulations focusing on a lubricant for hydrophilic matrix tablets

A robust experimental design method was developed with the well-established response surface methodology and time series modeling to facilitate the formulation development process with magnesium stearate incorporated into hydrophilic matrix tablets. Two directional analyses and a time-oriented model were utilized to optimize the experimental responses. Evaluations of tablet gelation and drug release were conducted with two factors x(1) and x(2): one was a formulation factor (the amount of magnesium stearate) and the other was a processing factor (mixing time), respectively. Moreover, different batch sizes (100 and 500 tablet batches) were also evaluated to investigate an effect of batch size. The selected input control factors were arranged in a mixture simplex lattice design with 13 experimental runs. The obtained optimal settings of magnesium stearate for gelation were 0.46 g, 2.76 min (mixing time) for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The optimal settings for drug release were 0.33 g, 7.99 min for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The exact ratio and mixing time of magnesium stearate could be formulated according to the resulting hydrophilic matrix tablet properties. The newly designed experimental method provided very useful information for characterizing significant factors and hence to obtain optimum formulations allowing for a systematic and reliable experimental design method.     

Evaluation of Ludipress as a “Multipurpose Excipient” for Direct Compression: Part II: Interactive Blending and Tableting with Micronized Glibenclamide

In the second part of this publication the differing interactions of micronized glibenclamide during mixing with four filler/binders for direct compression were studied. The excipients used were: Ludipress, Cellactose, Avicel PH 200 and Karion Instant. In order to prepare interactive mixtures, increasing amounts of micronized glibenclamide were blended with filler/binder fractions of 125 to 500 μm. The degree of interactivity was determined by air jet sifting of the mixes, comparing drug content in the mixes before and after sieving. Cellactose showed the highest adhesion tendency for glibenclamide due to the large cavities in the particles, leading to a reagglomeration within these cavities. Tablets containing 1.75, 3.50, 5.00 and 10.00 mg of glibenclamide per tablet were compressed with Cellactose and Ludipress. As previously reported (1) for Cellactose based placebo tablets, Cellactose also showed a tremendous increase in disintegration time and a prolonged dissolution rate at compaction pressures above 100 MPa. The corresponding values of Ludipress were not influenced. Therefore in terms of a multipurpose-excipient, Ludipress should be given preference in the formulation of low dosed drugs.     

Content Uniformity of a Low Dose Pharmaceutical Product

ABSTRACT

Optimum homogeneity and physical stability for a Roche compound (RO) low dose formulations (0,125 and 0.250 mg Tablets i.e. 0.07 to 0.14% w/w drug load, respectively) were achieved. Direct compression powder formulations were prepared by mixing the active drug substance with Starch 1500 (ST) to form an active pre-mix. Other ingredients were added subsequently. The final powder mix was subjected to a vibration of 4 Hz frequency using a specially designed segregation unit and content uniformity was assessed for these formulations. ST was considered superior to both lactose anhydrous and Avicel PH 102 in preparing homogeneous and physically stable mixes. Production-size batches of the product were successfully manufactured (Mean Drug content = 98 100%, RSV = 2%).     

Polydisperse powder mixtures: effect of particle size and shape on mixture stability

The effect of the shape and size of the components on the stability of mixtures was evaluated in binary mixtures of drug and carrier. Aspirin was used as model drug; spray-dried lactose and microcrystalline cellulose were used as carriers. The coefficient of variation (CV) of the drug in the mixture at various time intervals during mixing was used as a measure of homogeneity. The stability of mixtures was assessed under conditions that were conducive to segregation—in this case, prolonged mixing. The pattern of change in CV with time was analyzed in terms of convective, shear, and diffusive mixing stages. The variation resulting from a change in the shape of the carriers was smaller than that resulting from size differences. The segregation rate constant, calculated on the assumption of a first-order mixing process, was found to be larger in mixtures having components of different shape than in mixtures having components of similar shape. In mixtures of micronized drug and carrier, the pattern of change in the CV of drug with mixing time was attributed to the distribution of agglomerates of micronized drug during convective mixing, followed by shearing of agglomerates and, finally, the distribution of the primary particles during diffusive mixing. Mixtures of non-cohesive powders of similar size and shape behaved like random mixtures of non-interacting components.     

Surface Characterisation df Sucrose and Antibiotics Powder Mixes with Relevance to Mixing Theories

Adhesional ordered mixing is not applicable in real systems because ordered interaction between drug and excipient particles can not be achieved. In contrary, Interactive Mixture approach is more applicable because it allows the powder mixtures to be described according to the state of homogeneity achieved which is dependent on mixing variables.

Surface characteristics of powder mixture particles are important to study in order to understand the interparticulate interactions between drug and excipient particles.

Indentations on excipient particles act as mechanical entrapment sites for drug particles which result in areas containing highly localised drug content. Consequently, the state of homogeneity of powder mixtures is possibly affected. Furthermore, the release of particles which are entrapped will be different from those held by interparticulate forces on the plain surfaces of excipient particles. This is particularly important when the excipient particles are insoluble and drug particles are poorly soluble.     

Polydisperse Powder Mixtures: Effect of Particle Size and Shape on Mixture Stability

ABSTRACT

The effect of the shape and size of the components on the stability of mixtures was evaluated in binary mixtures of drug and carrier. Aspirin was used as model drug; spray-dried lactose and microcrystalline cellulose were used as carriers. The coefficient of variation (CV) of the drug in the mixture at various time intervals during mixing was used as a measure of homogeneity. The stability of mixtures was assessed under conditions that were conducive to segregation—in this case, prolonged mixing. The pattern of change in CV with time was analyzed in terms of convective, shear, and diffusive mixing stages. The variation resulting from a change in the shape of the carriers was smaller than that resulting from size differences. The segregation rate constant, calculated on the assumption of a first-order mixing process, was found to be larger in mixtures having components of different shape than in mixtures having components of similar shape. In mixtures of micronized drug and carrier, the pattern of change in the CV of drug with mixing time was attributed to the distribution of agglomerates of micronized drug during convective mixing, followed by shearing of agglomerates and, finally, the distribution of the primary particles during diffusive mixing. Mixtures of non-cohesive powders of similar size and shape behaved like random mixtures of non-interacting components.